The present invention is directed to synthetic routes to prepare aspartic protease inhibitors and in particular, hydroxyethyl amine inhibitors. The present invention is also directed to synthetic intermediates along those routes, and to the inhibitors, themselves. The use of parallel synthetic sequences to prepare focused chemical libraries directed toward a specific protein family, when leveraged by a suitably broad synthetic method, is a highly valuable approach for hit generation in drug discovery because a hit to any member of that protein family may be identified and the speed in which analogs may be prepared in a subsequent hit to lead program is substantially increased.
The aspartyl protease family includes: HIV protease, cathepsins, β-secretase, renin, and plasmepsin. A number of native and enzyme-inhibitor crystal structures have been solved for the above aspartic proteases. A key structural element in most inhibitors is a hydroxyl or hydroxyl like moiety that binds to the catalytically active aspartic acids in the enzyme active site. Work toward the development of mechanism pathway inhibitors for this family of enzymes has resulted in the identification of a number of transition-state analogue units, which are effective for inhibiting aspartic proteases.
Two of the most useful of these transition-state analogue units are the hydroxyethylene and hydroxyethylamine units; the later isostere has been employed extensively in agents for the treatment of AIDS and are currently used in clinical practice (Lebon, F.; Ledecq, M. Curr. Med. Chem. 2000, 7, 455-477).
Other solid-phase and/or parallel approaches to synthesis of hydroxyethyl amines have been described. Tamamura, H. et al., Org. Biomol. Chem. 2003, 1, 2468-2473 describe a solid phase synthesis of hydroxyethylamine dipeptide isosteres but do not describe or suggest the methods or compounds of the present invention. U.S. Pat. No. 6,150,416 to Kick et al. describes hydroxyethylamine compounds that bind cathepsin D, but does not describe or suggest the methods or compounds of the present invention. Kick, E. K.; Ellman, J. A. J. Med. Chem. 1995, 38, 1427-1430 describe the solid phase synthesis of hydroxyethylamino aspartyl protease inhibitors, but does not describe or suggest the methods or compounds of the present invention. Baker, C. T. et al., Bioorg. Med. Chem. Lett. 1998, 8, 3631-3636 also describe the solid phase synthesis of hydroxyethylamino aspartyl protease inhibitors, but does not describe or suggest the methods or compounds of the present invention. Chino, M. et al., Tetrahedron 2002, 58, 6305-6310 also describe the solid phase synthesis of hydroxyethylamino aspartyl protease inhibitors, but does not describe or suggest the methods or compounds of the present invention. None of these prior approaches provides as flexible or efficient a means of synthesizing hydroxyethyl amines as does the present invention
Dörner, B. et al. (Bioorg. Med. Chem. 1996, 4, 709-715) describe a solid-phase synthetic method for generating alkylated amides using nine successive cycles exposing a support-bound amide to lithium tert-butoxide followed by quenching with electrophile. Such a method, however, cannot provide the epoxyalkyl intermediates useful in the present invention in practical yields.
Thus, a solid phase method has been developed to generate hydroxyethylamino amides, a known aspartyl protease isostere. We have preformed the eight step sequence and obtained the resulting hydroxyethylamino amides in good yield without the need for rigorous exclusion of water or oxygen. The procedure draws on large reagent pools: carboxylic acids, 1° amines, and aldehydes; which results in a virtual library of over 1 trillion compounds. In addition, we have developed a general method for the monoalkylation of Rink type resins.